Early diagnostic value of survivin and its alternative splice variants in breast cancers.

Abstract

35 Background: The inhibitor of apoptosis (IAP) protein Survivin and its splice variants are differentially expressed in breast cancer tissues and have recently been shown to be released from tumor cells via small membrane-bound vesicles called exosomes. Tumor-derived exosomes play multiple roles in tumor growth and metastasis and may produce these functions by impacting immune escape, tumor invasion and angiogenesis. We, therefore, hypothesize that analysis of exosomal Survivin and its splice variants may provide a novel biomarker for early diagnosis of breast cancer in addition to current recommended methods. Methods: Twenty paired breast cancer patient’s sera and tumor tissue, and ten normal control sera were used for analysis. ELISA was performed to quantitate serum levels of Survivin. Exosomes were isolated from the sera using Exoquick. RT-PCR, western blots with densitometry, and immunohistochemistry followed by confocal microscopy were then performed. Results: For each breast cancer patient serum, Survivin levels were significantly higher compared to control (p<0.05). While Survivin and the DEx3 splice variant expression and localization were similar, differential expression of Survivin and the 2B splice variant protein and mRNA existed in the exosomes and tissue samples. Survivin and -DEx3 proteins were the predominant forms detected in 100% (20/20) of the breast cancer tissues evaluated, whereas a more variable expression of Survivin-2B, with enhanced levels found in areas of necrosis. We also for the first time here show the exosomal localization of Survivin and its splice variants DEx3 and 2B in sera from breast cancer patients. Conclusions: The result of the proposed project supports our hypothesis that differential expression of exosomal-Survivin and its alternative splice variants may serve as a diagnostic marker in breast cancer patients. For future direction, we plan to study the prognostic value of exosomal-Survivin and its splice variants on a large panel of primary breast cancers within a setting of well-followed clinical outcomes.

Breast cancer‐derived exosomes: Tumor progression and therapeutic agents

“…Additionally, the diverse expression pattern of exosomal Survivin-2B from the serum of patients with breast cancer may be used as a biomarker for patients with early breast cancer (Khan et al, 2012).…”

Liquid Biopsy Targeting Monocarboxylate Transporter 1 on the Surface Membrane of Tumor-Derived Extracellular Vesicles from Synovial Sarcoma

“…Emerging evidence has demonstrated the clinical utility of circulating EVs as a diagnostic, non-invasive biomarker in patients with malignant tumors. Several studies have demonstrated their potential in various cancers, including breast [ 26 , 27 , 28 , 29 ], prostate [ 30 , 31 ], pancreatic [ 32 ], ovarian [ 33 , 34 ], colorectal cancers [ 14 ], and glioblastoma [ 35 ] but the evidence is lacking in bone and soft-tissue sarcomas. In this study, we first demonstrate that circulating SS-derived EVs may represent a novel target for liquid biopsy of this aggressive disease.…”

“…The intensity of staining was scored semi-qualitatively as follows: 0, negative; 1, weak; 2, intermediate; and 3, strong. The final score was defined as the sum of both parameters (extension and intensity) and grouped as negative (score 0 and 2) and positive (score 3–6), as previously described [ 26 ].…”

Cancer-associated Fibroblasts Communicate with Breast Tumor Cells Through Extracellular Vesicles in Tumor Development

“… 69 Survivin is a member of the apoptosis inhibitor family that is expressed at high levels in breast cancer and regulates cell division and apoptosis. 70 , 71 Breast cancer cells-activated CAFs release exosomes that promote proliferation, migration, colony formation, and EMT in MDA-MB-231 and MCF-7 breast cancer cells; however, these events are not induced by EVs from mammary non-tumorigenic epithelial cells HBL-100. Moreover, an in vivo model using BALB/c-NU mice shows that survivin induces overexpression of SOD1 in CAFs to promote proliferation and metastasis, whereas SOD1 expression is higher in breast cancer women stage II, III, and IV compared with breast cancer women stage I .…”